A phase 3 randomized clinical trial has demonstrated significant improvements in overall survival with the addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab in patients with early-stage triple-negative breast cancer. The final results of the KEYNOTE-522 trial were published in the November 28, 2024 issue of The New England Journal of Medicine.
This international, double-blind, placebo-controlled study was conducted at 181 sites plus 2 satellite sites across 21 countries in Europe, North America, Asia, and Latin America. The trial was funded by Merck Sharp and Dohme, a subsidiary of Merck.
The purpose of the study was to evaluate the efficacy and safety of adding the PD-1 inhibitor pembrolizumab to standard neoadjuvant chemotherapy followed by adjuvant pembrolizumab in patients with previously untreated stage II or III triple-negative breast cancer. Triple-negative breast cancer lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, making it challenging to treat and associated with poorer outcomes compared to other breast cancer subtypes.
A total of 1174 patients were enrolled in the trial between March 2017 and September 2018. Eligible patients had centrally confirmed triple-negative breast cancer that was newly diagnosed and previously untreated. Patients were required to have stage T1c N1-2 or T2-4 N0-2 disease as assessed by the investigator, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were eligible regardless of PD-L1 expression status.
Patients were randomly assigned in a 2:1 ratio to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles.
The primary endpoints were pathological complete response and event-free survival. Overall survival was a key secondary endpoint. At the data cutoff of March 22, 2024, the median follow-up was 75.1 months.
The study met its primary endpoints, with significant improvements in both pathological complete response and event-free survival with pembrolizumab plus chemotherapy compared to chemotherapy alone, as previously reported. In this final analysis, pembrolizumab plus chemotherapy also demonstrated a statistically significant improvement in overall survival.
The estimated 5-year overall survival rate was 86.6% in the pembrolizumab-chemotherapy group compared to 81.7% in the placebo-chemotherapy group (P=0.002). This represents an absolute improvement of 4.9 percentage points with the addition of pembrolizumab. The benefit in overall survival was observed across most prespecified subgroups, including those defined by PD-L1 expression status, nodal involvement, and tumor size.
Updated event-free survival data showed a 35% reduction in the risk of disease progression precluding definitive surgery, local or distant recurrence, second primary cancer, or death from any cause with pembrolizumab plus chemotherapy (hazard ratio 0.65; 95% CI 0.51-0.83). The 5-year event-free survival rate was 81.2% with pembrolizumab-chemotherapy versus 72.2% with placebo-chemotherapy, an absolute improvement of 9.0 percentage points.
The safety profile was consistent with previous reports and the known safety profiles of pembrolizumab and chemotherapy. Grade 3 or higher treatment-related adverse events occurred in 77.1% of patients in the pembrolizumab-chemotherapy group and 73.3% in the placebo-chemotherapy group. As expected, immune-mediated adverse events were more common with pembrolizumab, occurring in 35.0% of patients versus 13.1% with placebo. These were primarily driven by endocrinopathies and were generally low grade and manageable.
The authors concluded that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a statistically significant and clinically meaningful improvement in overall survival compared to neoadjuvant chemotherapy alone in patients with early-stage triple-negative breast cancer. The survival benefit was observed regardless of PD-L1 expression status.
Some limitations of the study include the lack of adjuvant capecitabine in the treatment protocol, as results showing a survival benefit with adjuvant capecitabine were reported after this trial was designed. Additionally, the trial was not designed to discern the relative efficacy contributions of the neoadjuvant versus adjuvant pembrolizumab treatment phases. Subgroup analyses were exploratory and results in small subgroups should be interpreted cautiously.
These results have significant potential clinical impact, providing further support for pembrolizumab plus neoadjuvant chemotherapy followed by adjuvant pembrolizumab as a new standard of care for high-risk, early-stage triple-negative breast cancer. The findings are particularly notable given that recurrences in triple-negative breast cancer tend to occur earlier than in other breast cancer subtypes, with up to 90% occurring in the first 5 years.
The sustained benefit in event-free survival and significant improvement in overall survival after more than 6 years of follow-up demonstrate the potential for immunotherapy to provide long-term disease control in this aggressive breast cancer subtype. The results also suggest the overall survival benefit may exceed that expected from the improvement in pathological complete response alone, potentially related to changes in tumor biology or the impact of adjuvant pembrolizumab.
While the addition of pembrolizumab increased immune-mediated adverse events, these were generally manageable. However, clinicians should be vigilant in monitoring for and appropriately managing these events, particularly given the curative-intent setting. Continued follow-up will be important to assess for any late immune-related toxicities.
In summary, this landmark phase 3 trial provides high-level evidence supporting the integration of immunotherapy into the standard neoadjuvant and adjuvant treatment approach for early-stage triple-negative breast cancer. The significant improvements in pathological complete response, event-free survival, and now overall survival establish a new benchmark for outcomes in this high-risk patient population.
References
Schmid P, Cortes J, Dent R, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med. 2024;391(21):1981-1991. doi:10.1056/NEJMoa2409932
